The over-arching theme of this Program is taking cutting edge technologies for genomics, proteomics and genetics and applying these tools rigorously and critically to the major challenges of transplantation immunology and biology. These efforts in functional genomics are designed to accomplish three complementary objectives: 1) biological discovery, 2) biomarker discovery, and 3) translation of these discoveries to enhance the safety and efficacy of clinical practices in kidney and heart transplantation. All of us believe that the best of translational medicine is advanced by the best of basic research. We believe that serious efforts to achieve fundamental biological understanding of molecular mechanisms must be driven by highly organized teams of scientists and physicians working in close concert. When such collaborative relationships bring science and medicine together successfully, the resulting basic but clinically informed knowledge can be translated directly to preserving health and conquering disease. That effort is what gives meaning to everything we have done in the last funding period and propose to do now. There are many scientific and clinical hypotheses detailed in the individual Projects and Cores. But the central hypothesis of this Program is that multi-dimensional functional genomics will allow us to see the connections between the multiple, parallel mechanisms of immunity that are triggered at the time of a transplant and then evolve in time. In fact, it is this evolution in time that determines the ultimate clinical outcome of the transplant. Thus, if early injury is incompletely repaired, if the immune response determined by both donor and recipient genetics is reactive and progressive or dysregulated, if antibodies are generated and if immunosuppression is ineffective or inadequate for any reason, these elements will drive a progressive, immune/inflammatory destruction of the transplant. It is our mission to minimize this kind of outcome. To achieve this mission we plan to go from basic biology to biomarker signatures validated clinically for diagnosis and prediction of transplant outcomes. Ultimately, we hope to create the genomic tools that will allow physicians to optimize and personalize the safety and efficacy of immunosuppression.